Reply: Cautious interpretation of the association between finite treatment and better prognosis in initially HBeAg-negative hepatitis B patients with cirrhosis
Authors: Wen-Juei Jeng, Rong-Nan Chien, Yun-Fan Liaw
Journal: Hepatology (2023)

We appreciate Deng et al1 for their comments and the opportunity for clarification. To minimize bias, we set the end of nucleos(t)ide analog (Nuc) treatment (finite group) and 3-year-on-Nuc (continued group) as time 0 for propensity score matching.2 This could be the best method second to randomized controlled trials. The beneficial results of our study assessing/comparing hard end points, namely HCC and mortality ascertained by the national death database, have provided strong evidence to support Asian-Pacific guidelines for the strategy of finite Nuc therapy, including patients with cirrhosis.3 Hopefully, with this new evidence, Western experts will accept this strategy in their guidelines in the near future. For safety issues, our study showed self-discontinuation and lost-to-follow-up/monitoring in 20% of continued-group patients. Three of the continued-group patients versus 5 of the finite-group patients died of severe flare-related hepatic decompensation. As detailed in Table 1, the rates of non-HCC liver–related death/transplantation were not higher in the finite group. If these fatal patients were not lost-to-follow-up or had adhered to medication or the monitoring schedule, the tragic events could have been prevented/reduced by timely retreatment. TABLE 1 - Liver-related death/LT in finite group versus continued group Continued group, N: 593, n (%) Finite group, N: 494, n (%) p Liver-related mortality/LT 47 (8.0) 18 (3.6) 0.0030 HCC 31a 11 0.0106 Non-HCC 16 (2.7) 7 (1.4) 0.1439 Cirrhotic complications 8 (1.3) 1 (0.2) By ascertainmentb 5 (0.8) 1 (0.2) 0.8454 8 (1.3) 6 (1.2) Documented hepatitis flare 3c (0.5) 5d (1.0) 0.5381 aTwo patients with nonadvanced HCC died of cirrhotic complications.bDied elsewhere other than our sites; lack relevant information to rule out severe flare-related liver death.cTwo LTFU and 1 with poor adherence arrived in the emergency unit with severe flare.dOne with severe flare after flu, 1 after herbal medicine use, and 3 not adhering to monitoring schedule.Abbreviation: LT, liver transplant; LTFU, lost-to-follow-up; N, number. As to the low viremia status, it is different between that after Nuc withdrawal and that during continued Nuc therapy. The finite-group patients had had 3-year Nuc therapy and might have achieved immune restoration, which operates continuously after Nuc cessation and is further enhanced by relapsed viremia elicitation. In contrast, low viremia during long-term Nuc therapy might be the result of poor adherence.4,5 Notably, the finite group had achieved significantly greater annual HBsAg decline, lower end of follow-up quantitative HBsAg level (qHBsAg), more often <100 IU/mL, and HBsAg loss.2 The beneficial, virtuous cycle of the reciprocal effect on each other between the declining qHBsAg and immune response was speculated as the driving force for the much higher HBsAg loss rate and lower HCC incidence. In conclusion, the beneficial effects of our study are the results of a carefully conducted large study and have provided strong evidence for the strategy of finite Nuc therapy in patients with cirrhosis, a strategy that not merely treats the "virus" but also restores/enhances the host's immune response as part of the treatment strategy.